Methyl oxazole orexin receptor antagonists

ABSTRACT

The present invention is directed to methyloxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US2015/062888, filed Nov. 30, 2015, whichclaims priority from PCT Application No. PCT/CN2014/092804, filed Dec.2, 2014.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: orexin A (OX-A) (a 33 amino acid peptide) and orexin B(OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell, 1998, 92,573-585). Orexins are found to stimulate food consumption in ratssuggesting a physiological role for these peptides as mediators in thecentral feedback mechanism that regulates feeding behavior (Sakurai T.et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleep andwakefulness opening potentially novel therapeutic approaches fornarcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999,98, 437-451). Orexins have also been indicated as playing a role inarousal, reward, learning and memory (Harris, et al., Trends Neurosci.,2006, 29 (10), 571-577). Two orexin receptors have been cloned andcharacterized in mammals. They belong to the super family of G-proteincoupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): theorexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2receptor (OX2 or OX2R) is capable of binding OX-A as well as OX-B. Thephysiological actions in which orexins are presumed to participate arethought to be expressed via one or both of OX1 receptor and OX2 receptoras the two subtypes of orexin receptors.

SUMMARY OF THE INVENTION

The present invention is directed to methyloxazole compounds which areantagonists of orexin receptors. The present invention is also directedto uses of the compounds described herein in the potential treatment orprevention of neurological and psychiatric disorders and diseases inwhich orexin receptors are involved. The present invention is alsodirected to compositions comprising these compounds. The presentinvention is also directed to uses of these compositions in thepotential prevention or treatment of such diseases in which orexinreceptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:A is selected from the group consisting of phenyl, naphthyl andheteroaryl;each of R^(1a), R^(1b) and R^(1c) is independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1        (wherein if m is 0 or n is 0, a bond is present) and where the        alkyl is unsubstituted or substituted with one to three        substituents independently selected from R⁴,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one to three substituents        selected from R⁴,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one to three substituents independently        selected from R⁴,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one to three substituents independently        selected from R⁴,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where        the phenyl or naphthyl is unsubstituted or independently        substituted with one to three substituents independently        selected from R⁴,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one to three substituents        independently selected from R⁴,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently        selected from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with            R⁴,        -   (c) C₃₋₆alkenyl, which is unsubstituted or substituted with            R⁴,        -   (d) C₃₋₆alkynyl, which is unsubstituted or substituted with            R⁴,        -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted            with R⁴,        -   (f) phenyl, which is unsubstituted or substituted with R⁴,            and        -   (g) heterocycle, which is unsubstituted or substituted with            R⁴,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is        selected from the definitions of R¹⁰ and R¹¹,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R⁴ is selected from the group consisting of:    -   (1) hydroxyl,    -   (2) halogen,    -   (3) C₁₋₆alkyl,    -   (4) —C₃₋₆cycloalkyl,    -   (5) —O—C₁₋₆alkyl,    -   (6) —O(C═O)—C₁₋₆alkyl,    -   (7) —NH₂,    -   (8) —NH—C₁₋₆alkyl,    -   (9) —NO₂,    -   (10) phenyl,    -   (11) heterocycle,    -   (12) —CO₂H, and    -   (13) —CN;        R⁵ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl, —O—C₁₋₆alkyl, —NH₂, —NH—C₁₋₆alkyl,        —(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl is        unsubstituted or substituted with C₁₋₆alkyl, halogen, or        C₁₋₆alkyl-OH,    -   (4) C₃₋₆cycloalkyl, which is unsubstituted or substituted with        C₁₋₆alkyl, halogen, hydroxyl, —O—C₁₋₆alkyl, —NH₂, —NH—C₁₋₆alkyl,        —(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl is        unsubstituted or substituted with C₁₋₆alkyl, halogen, or        C₁₋₆alkyl-OH,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (6) —(C═O)O—C₁₋₆alkyl,    -   (7) —CN,    -   (8) —(C═O)NH₂,    -   (9) —(C═O)NH—C₁₋₆alkyl, and    -   (10) —(C═O)NH—O—C₁₋₆alkyl;        R⁶ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl, —O—C₁₋₆alkyl, —NH₂, —NH—C₁₋₆alkyl,        —(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl is        unsubstituted or substituted with C₁₋₆alkyl, halogen, or        C₁₋₆alkyl-OH,    -   (4) C₃₋₆cycloalkyl, which is unsubstituted or substituted with        C₁₋₆alkyl, halogen, hydroxyl, —O—C₁₋₆alkyl, —NH₂, —NH—C₁₋₆alkyl,        —(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl is        unsubstituted or substituted with C₁₋₆alkyl, halogen, or        C₁₋₆alkyl-OH,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) —(C═O)O—C₁₋₆alkyl,    -   (7) —CN,    -   (8) —(C═O)NH₂,    -   (9) —(C═O)NH—C₁₋₆alkyl, and    -   (10) —(C═O)NH—O—C₁₋₆alkyl;        or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein R^(1a), R^(1b), R^(1c), R⁵, and R⁶ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa′:

wherein R^(1a), R^(1b), R^(1c), R⁵, and R⁶ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa″:

wherein R^(1a), R^(1b), R^(1c), R⁵, and R⁶ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein R^(1a), R^(1b), R⁵, and R⁶ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb′:

wherein R^(1a), R^(1b), R⁵, and R⁶ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb″:

wherein R^(1a), R^(1b), R⁵, and R⁶ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc:

wherein R^(1a), R⁵, and R⁶ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc′:

wherein R^(1a), R⁵, and R⁶ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc″:

wherein R^(1a), R⁵, and R⁶ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds wherein A isselected from phenyl, pyridyl, thiophenyl, thiazolyl, isothiazolyl, andpyrazolyl. An embodiment of the present invention includes compoundswherein A is phenyl. An embodiment of the present invention includescompounds wherein A is pyridyl. An embodiment of the present inventionincludes compounds wherein A is thiophenyl. An embodiment of the presentinvention includes compounds wherein A is thiazolyl. An embodiment ofthe present invention includes compounds wherein A is isothiazolyl. Anembodiment of the present invention includes compounds wherein A ispyrazolyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from triazolyl,        tetrazolyl, oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl,        and pyrimidinyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (9) —CN, and    -   (10) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        and —O—C₁₋₆alkyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) —CN, and    -   (7) heteroaryl, wherein heteroaryl is selected from triazolyl,        tetrazolyl, oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl,        and pyrimidinyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen,    -   (5) —CN, and    -   (6) heteroaryl, wherein heteroaryl is selected from triazolyl,        oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl, and        pyrimidinyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, and R^(1a) and R^(1b) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) bromo,    -   (5) methyl,    -   (6) ethyl,    -   (7) trifluoromethyl, and    -   (8) heteroaryl, wherein heteroaryl is selected from triazolyl,        oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl, and        pyrimidinyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, R^(1b) is hydrogen, and R^(1a) is independently selectedfrom the group consisting of:

-   -   (1) triazolyl,    -   (2) tetrazolyl,    -   (3) oxazolyl,    -   (4) pyrrolyl,    -   (5) imidazolyl,    -   (6) pyridyl, and    -   (7) pyrimidinyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, R^(1b) is hydrogen, and R^(1a) is independently selectedfrom the group consisting of:

-   -   (1) triazolyl,    -   (2) tetrazolyl, and    -   (3) pyrimidinyl.

An embodiment of the present invention includes compounds wherein R⁵ isselected from the group consisting of:

-   -   (1) hydrogen,    -   (2) bromo,    -   (3) methyl,    -   (4) —C(CH₃)₂OH,    -   (5) —CH(OH)CH₃,    -   (6) —C(CH₃)(OH)CH₂CH₃,    -   (7) —CH₂OCH₃,    -   (8) cyclopropyl, and    -   (9) phenyl.

An embodiment of the present invention includes compounds wherein R⁵ is—C(CH₃)₂OH. An embodiment of the present invention includes compoundswherein R⁵ is —C(CH₃)(OH)CH₂CH₃.

An embodiment of the present invention includes compounds wherein R⁶ isselected from the group consisting of:

-   -   (1) hydrogen,    -   (2) bromo,    -   (3) methyl,    -   (4) trifluoromethyl,    -   (5) —CH(CH₃)₂, and    -   (6) phenyl.

An embodiment of the present invention includes compounds wherein R⁶ ismethyl.

An embodiment of the present invention includes compounds wherein atleast one of R⁵ and R⁶ is other than hydrogen.

Certain embodiments of the present invention include a compound which isselected from the group consisting of the subject compounds of theExamples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without specificstereochemistry.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₆alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents. The term “heterocycle” as used herein includes bothunsaturated and saturated heterocyclic moieties, wherein the unsaturatedheterocyclic moieties (i.e. “heteroaryl”) include benzoimidazolyl,benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, andwherein the saturated heterocyclic moieties include azetidinyl,1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

The present invention also includes all pharmaceutically acceptableisotopic variations of a compound of the Formula I in which one or moreatoms is replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes suitable for inclusion inthe compounds of the invention include isotopes of hydrogen such as ²Hand ³H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N,oxygen such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus such as ³²P, sulfur such as³⁵S, fluorine such as ¹⁸F, iodine such as ¹²³I and ¹²⁵I, and chlorinesuch as ³⁶Cl. Certain isotopically-labelled compounds of Formula I, forexample those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection. Substitution with heavier isotopes such as deuterium, i.e.²H, may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labelled compoundsof Formula I can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples using appropriate isotopically-labelledreagents in place of the non-labelled reagent previously employed.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includethe ammonium, calcium, magnesium, potassium, and sodium salts. Salts inthe solid form may exist in more than one crystal structure, and mayalso be in the form of hydrates. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particular embodiments include the citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which is selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual enantiomers or diastereomersthereof.

The present invention is also directed to the use of the compoundsdisclosed herein as antagonists of orexin receptor activity. The subjectcompounds and pharmaceutically acceptable salts thereof are useful in amethod of antagonizing orexin receptor activity in a subject such as amammal comprising the administration of an amount of the compound. Inaddition to primates, especially humans, a variety of other mammals maybe administered with a compound of the present invention. The presentinvention is directed to a compound of the present invention or apharmaceutically acceptable salt thereof that could be useful intherapy. The present invention may further be directed to a use of acompound of the present invention or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for antagonizing orexinreceptor activity or treating the disorders and diseases noted herein inhumans and animals.

A subject administered with a compound of the present invention, or apharmaceutically acceptable salt thereof, is generally a mammal, such asa human being, male or female. The amount of compound administered tothe subject is an amount sufficient to antagonize the orexin receptor inthe subject. In an embodiment, the amount of compound can be an“effective amount”, wherein the subject compound is administered in anamount that will elicit the biological or medical response of a tissue,system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician. An effective amountdoes not necessarily include considerations of toxicity and safetyrelated to the administration of the compound. It is recognized that oneskilled in the art may affect neurological and psychiatric disordersassociated with orexin receptor activation by treating a subjectpresently afflicted with the disorders, or by prophylactically treatinga subject likely to be afflicted with the disorders, with an effectiveamount of a compound of the present invention. As used herein, the terms“treatment” and “treating” refer to all processes wherein there may be aslowing, interrupting, arresting, controlling, or stopping of theprogression of the neurological and psychiatric disorders describedherein, but does not necessarily indicate a total elimination of alldisorder symptoms, as well as the prophylactic therapy of the mentionedconditions, particularly in a subject that is predisposed to suchdisease or disorder. The terms “administration of” and or “administeringa” compound should be understood to mean providing a compound of theinvention or a prodrug of a compound of the invention to the subject.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term isintended to encompass a product comprising the active ingredient(s), andthe inert ingredient(s) that make up the carrier, as well as any productwhich results, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thecompositions of the present invention encompass any composition made byadmixing a compound of the present invention and a pharmaceuticallyacceptable carrier. By “pharmaceutically acceptable” it is meant thecarrier, diluent or excipient must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The utility of the compounds in accordance with the present invention asorexin receptor OX1R and/or OX2R antagonists may be readily determinedwithout undue experimentation by methodology well known in the art,including the “FLIPR Ca²⁺ Flux Assay” (Okumura et al., Biochem. Biophys.Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2receptor antagonistic activity of the compounds of the present inventionwas determined in accordance with the following experimental method. Forintracellular calcium measurements, Chinese hamster ovary (CHO) cellsexpressing the rat orexin-1 receptor or the human orexin-2 receptor, aregrown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/mlG418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100μg/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). Thecells are seeded at 20,000 cells/well into Becton-Dickinson black384-well clear bottom sterile plates coated with poly-D-lysine. Allreagents were from GIBCO-Invitrogen Corp. The seeded plates areincubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as theagonist is prepared as a 1 mM stock solution in 1% bovine serum albumin(BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSAand 2.5 mM probenecid, pH7.4) for use in the assay at a finalconcentration of 70 pM. Test compounds are prepared as 10 mM stocksolution in DMSO, then diluted in 384-well plates, first in DMSO, thenassay buffer. On the day of the assay, cells are washed 3 times with 100μl assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 μlassay buffer containing 1 pM Fluo-4AM ester, 0.02% pluronic acid, and 1%BSA. The dye loading solution is then aspirated and cells are washed 3times with 100 μl assay buffer. 30 μl of that same buffer is left ineach well. Within the Fluorescent Imaging Plate Reader (FLIPR, MolecularDevices), test compounds are added to the plate in a volume of 25 μl,incubated for 5 min and finally 25 μl of agonist is added. Fluorescenceis measured for each well at 1 second intervals for 5 minutes and theheight of each fluorescence peak is compared to the height of thefluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer inplace of antagonist. For each antagonist, IC50 value (the concentrationof compound needed to inhibit 50% of the agonist response) isdetermined. Alternatively, compound potency can be assessed by aradioligand binding assay (described in Bergman et. al. Bioorg. Med.Chem. Lett. 2008, 18, 1425-1430) in which the inhibition constant(K_(i)) is determined in membranes prepared from CHO cells expressingeither the OX1 or OX2 receptor. The intrinsic orexin receptor antagonistactivity of a compound which may be used in the present invention may bedetermined by these assays.

All of the final compounds of the following examples had activity inantagonizing the human orexin-2 receptor in the aforementioned assayswith an IC₅₀ of about 0.1 nM to 2500 nM. All of the final compounds ofthe following examples had activity in the FLIPR assay with an IC50 ofabout 5 nM to 2500 nM against the orexin-2 receptor. Additional data isprovided in the following Examples. Such a result is indicative of theintrinsic activity of the compounds in use as antagonists of orexin-1receptor and/or the orexin-2 receptor. In general, one of ordinary skillin the art would appreciate that a substance is considered toeffectively antagonize the orexin receptor if it has an IC50 of lessthan about 50 μM, or more specifically less than about 1000 nM.

The orexin receptors have been implicated in a wide range of biologicalfunctions. This has suggested a potential role for these receptors in avariety of disease processes in humans or other species. The compoundsof the present invention could therefore potentially have utility intreating, preventing, ameliorating, controlling or reducing the risk ofa variety of neurological and psychiatric disorders associated withorexin receptors, including one or more of the following conditions ordiseases: sleep disorders, sleep disturbances, including enhancing sleepquality, improving sleep quality, increasing sleep efficiency,augmenting sleep maintenance; increasing the value which is calculatedfrom the time that a subject sleeps divided by the time that a subjectis attempting to sleep; improving sleep initiation; decreasing sleeplatency or onset (the time it takes to fall asleep); decreasingdifficulties in falling asleep; increasing sleep continuity; decreasingthe number of awakenings during sleep; decreasing intermittent wakingsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; decreasing nocturnalarousals, especially early morning awakenings; increasing daytimealertness; reducing daytime drowsiness; treating or reducing excessivedaytime sleepiness; increasing satisfaction with the intensity of sleep;increasing sleep maintenance; idiopathic insomnia; sleep problems;insomnia, hypersomnia, idiopathic hypersomnia, repeatabilityhypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleepapnea, wakefulness, nocturnal myoclonus, REM sleep interruptions,jet-lag, shift workers' sleep disturbances, dyssomnias, night terror,insomnias associated with depression, emotional/mood disorders,Alzheimer's disease or cognitive impairment, as well as sleep walkingand enuresis, and sleep disorders which accompany aging; Alzheimer'ssundowning; conditions associated with circadian rhythmicity as well asmental and physical disorders associated with travel across time zonesand with rotating shift-work schedules, conditions due to drugs whichcause reductions in REM sleep as a side effect; fibromyalgia; syndromeswhich are manifested by non-restorative sleep and muscle pain or sleepapnea which is associated with respiratory disturbances during sleep;conditions which result from a diminished quality of sleep; increasinglearning; augmenting memory; increasing retention of memory; eatingdisorders associated with excessive food intake and complicationsassociated therewith, compulsive eating disorders, obesity (due to anycause, whether genetic or environmental), obesity-related disordersovereating, anorexia, bulimia, cachexia, dysregulated appetite control,hypertension, diabetes, elevated plasma insulin concentrations andinsulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast,prostate and colon cancer, osteoarthritis, obstructive sleep apnea,cholelithiasis, gallstones, heart disease, lung disease, abnormal heartrhythms and arrythmias, myocardial infarction, congestive heart failure,coronary heart disease, acute and congestive heart failure; hypotension;hypertension; urinary retention; osteoporosis; angina pectoris;myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoidhaemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronicrenal failure; renal disease; impaired glucose tolerance; sudden death,polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g., children with acutelymphoblastic leukemia, metabolic syndrome, also known as syndrome X,insulin resistance syndrome, reproductive hormone abnormalities, sexualand reproductive dysfunction, such as impaired fertility, infertility,hypogonadism in males and hirsutism in females, fetal defects associatedwith maternal obesity, gastrointestinal motility disorders, intestinalmotility dyskinesias, obesity-related gastro-esophageal reflux,hypothalmic diseases, hypophysis diseases, respiratory disorders, suchas obesity-hypoventilation syndrome (Pickwickian syndrome),breathlessness, cardiovascular disorders, inflammation, such as systemicinflammation of the vasculature, arteriosclerosis, hypercholesterolemia,hyperuricaemia, lower back pain, gallbladder disease, gout, kidneycancer, increased anesthetic risk, reducing the risk of secondaryoutcomes of obesity, such as reducing the risk of left ventricularhypertrophy; diseases or disorders where abnormal oscillatory activityoccurs in the brain, including depression, migraine, neuropathic pain,Parkinson's disease, psychosis and schizophrenia, as well as diseases ordisorders where there is abnormal coupling of activity, particularlythrough the thalamus; enhancing cognitive function, including cognitivedysfunctions that comprise deficits in all types of attention, learningand memory functions occurring transiently or chronically in the normal,healthy, young, adult or aging population, and also occurringtransiently or chronically in psychiatric, neurologic, cardiovascularand immune disorders; enhancing memory; increasing memory retention;increasing immune response; increasing immune function; hot flashes;night sweats; extending life span; schizophrenia; muscle-relateddisorders that are controlled by the excitation/relaxation rhythmsimposed by the neural system such as cardiac rhythm and other disordersof the cardiovascular system; conditions related to proliferation ofcells such as vasodilation or vasorestriction and blood pressure;cancer; cardiac arrhythmia; hypertension; congestive heart failure;conditions of the genital/urinary system; disorders of sexual functionand fertility; adequacy of renal function; responsivity to anesthetics;mood disorders, such as depression or more particularly depressivedisorders, for example, single episodic or recurrent major depressivedisorders and dysthymic disorders, or bipolar disorders, for example,bipolar I disorder, bipolar II disorder and cyclothymic disorder, mooddisorders due to a general medical condition, and substance-induced mooddisorders; affective neurosis; depressive neurosis; anxiety neurosis;anxiety disorders including acute stress disorder, agoraphobia,generalized anxiety disorder, obsessive-compulsive disorder, panicattack, panic disorder, post-traumatic stress disorder, separationanxiety disorder, social phobia, specific phobia, substance-inducedanxiety disorder and anxiety due to a general medical condition; acuteneurological and psychiatric disorders such as cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, ischemicstroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington'sChorea; Huntington's disease and Tourette syndrome; Cushing'ssyndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia;hypophysis tumor/adenoma; hypothalamic diseases; inflammatory boweldisease; gastric diskinesia; gastric ulcers; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; amyotrophic lateralsclerosis; multiple sclerosis; ocular damage; retinopathy; cognitivedisorders; idiopathic and drug-induced Parkinson's disease; muscularspasms and disorders associated with muscular spasticity includingtremors, epilepsy, convulsions, seizure disorders, absence seisures,complex partial and generalized seizures; Lennox-Gastaut syndrome;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, trauma, vascular problems or stroke, HIV disease,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jacob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium, amnestic disorders or agerelated cognitive decline; schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-inducedpsychotic disorder; dissociative disorders including multiplepersonality syndromes and psychogenic amnesias; substance-relateddisorders, substance use, substance abuse, substance seeking, substancereinstatement, all types of psychological and physical addictions andaddictive behaviors, reward-related behaviors (includingsubstance-induced delirium, persisting dementia, persisting amnesticdisorder, psychotic disorder or anxiety disorder; tolerance, addictivefeeding, addictive feeding behaviors, binge/purge feeding behaviors,dependence, withdrawal or relapse from substances including alcohol,amphetamines, cannabis, cocaine, hallucinogens, inhalants, morphine,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);appetite, taste, eating or drinking disorders; movement disorders,including akinesias and akinetic-rigid syndromes (including Parkinson'sdisease, drug-induced parkinsonism, postencephalitic parkinsonism,progressive supranuclear palsy, multiple system atrophy, corticobasaldegeneration, parkinsonism-ALS dementia complex and basal gangliacalcification), chronic fatigue syndrome, fatigue, including Parkinson'sfatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorderor a circadian rhythm disorder, medication-induced parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias[including tremor (such as rest tremor, essential tremor, posturaltremor and intention tremor), chorea (such as Sydenham's chorea,Huntington's disease, benign hereditary chorea, neuroacanthocytosis,symptomatic chorea, drug-induced chorea and hemiballism), myoclonus(including generalised myoclonus and focal myoclonus), tics (includingsimple tics, complex tics and symptomatic tics), restless leg syndromeand dystonia (including generalised dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp and hemiplegic dystonia); neurodegenerativedisorders including nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders;attention deficit/hyperactivity disorder (ADHD); conduct disorder;migraine (including migraine headache); headache; hyperalgesia; pain;enhanced or exaggerated sensitivity to pain such as hyperalgesia,causalgia, and allodynia; acute pain; burn pain; atypical facial pain;neuropathic pain; back pain; complex regional pain syndrome I and II;arthritic pain; sports injury pain; pain related to infection e.g. HIV,post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers;Kallman's syndrome (anosmia); asthma; cancer; conditions associated withvisceral pain such as irritable bowel syndrome, and angina; eatingdisorders; urinary incontinence; substance tolerance, substancewithdrawal (including, substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,etc.); psychosis; schizophrenia; anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder); mooddisorders (including depression, mania, bipolar disorders); trigeminalneuralgia; hearing loss; tinnitus; neuronal damage including oculardamage; retinopathy; macular degeneration of the eye; emesis; brainedema; pain, including acute and chronic pain states, severe pain,intractable pain, inflammatory pain, neuropathic pain, post-traumaticpain, bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain, neuropathic pain, post-traumatic pain, trigeminalneuralgia, migraine and migraine headache and other diseases related togeneral orexin system dysfunction.

Thus, in certain embodiments the present invention may provide methodsfor: enhancing the quality of sleep; augmenting sleep maintenance;increasing REM sleep; increasing stage 2 sleep; decreasing fragmentationof sleep patterns; treating insomnia and all types of sleep disorders;treating or controlling sleep disturbances associated with diseases suchas neurological disorders including neuropathic pain and restless legsyndrome; treating or controlling addiction disorders; treating orcontrolling psychoactive substance use and abuse; enhancing cognition;increasing memory retention; treating or controlling obesity; treatingor controlling diabetes and appetite, taste, eating, or drinkingdisorders; treating or controlling hypothalamic diseases; treating orcontrolling depression; treating, controlling, ameliorating or reducingthe risk of epilepsy, including absence epilepsy; treating orcontrolling pain, including neuropathic pain; treating or controllingParkinson's disease; treating or controlling psychosis; treating orcontrolling dysthymic, mood, psychotic and anxiety disorders; treatingor controlling depression, including major depression and majordepression disorder; treating or controlling bipolar disorder; ortreating, controlling, ameliorating or reducing the risk ofschizophrenia, in a mammalian subject which comprises administering tothe subject a compound of the present invention.

The subject compounds could further be of potential use in a method forthe prevention, treatment, control, amelioration, or reduction of riskof the diseases, disorders and conditions noted herein. The dosage ofactive ingredient in the compositions of this invention may be varied,however, it is necessary that the amount of the active ingredient besuch that a suitable dosage form is obtained. The active ingredient maybe administered to subjects (animals and human) in need of suchtreatment in dosages that will provide optimal pharmaceutical efficacy.The selected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from subject to subject depending upon the nature and severityof disease, the patient's weight, special diets then being followed by asubject, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.0001 to 10mg/kg. of body weight daily are administered to the subject, e.g.,humans and elderly humans, to obtain effective antagonism of orexinreceptors. The dosage range will generally be about 0.5 mg to 1.0 g. persubject per day which may be administered in single or multiple doses.In one embodiment, the dosage range will be about 0.5 mg to 500 mg persubject per day; in another embodiment about 0.5 mg to 200 mg persubject per day; and in yet another embodiment about 5 mg to 50 mg persubject per day. Pharmaceutical compositions of the present inventionmay be provided in a solid dosage formulation such as comprising about0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mgactive ingredient. The pharmaceutical composition may be provided in asolid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the subject to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day. The compounds may be administered beforebedtime. For example, the compounds may be administered about 1 Hourprior to bedtime, about 30 minutes prior to bedtime or immediatelybefore bedtime.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includetherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, such as about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The compounds of the present invention may be administered incombination with other compounds which are known in the art to be usefulfor enhancing sleep quality and preventing and treating sleep disordersand sleep disturbances, including e.g., sedatives, hypnotics,anxiolytics, antipsychotics, antianxiety agents, antihistamines,benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists,histamine antagonists including histamine H3 antagonists, histamine H3inverse agonists, imidazopyridines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, other orexin antagonists,such as suvorexant, orexin agonists, prokineticin agonists andantagonists, pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, ornortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide,secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine,tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam,trepipam, tricetamide, triclofos, trifluoperazine, trimetozine,trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone,zolpidem, and salts thereof, and combinations thereof, and the like, orthe compound of the present invention may be administered in conjunctionwith the use of physical methods such as with light therapy orelectrical stimulation.

In another embodiment, the subject compound may be employed incombination with other compounds which are known in the art, eitheradministered separately or in the same pharmaceutical compositions,including, but are not limited to: insulin sensitizers including (i)PPARγ antagonists such as glitazones (e.g. ciglitazone; darglitazone;englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone;troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641,and LY-300512, and the like); (iii) biguanides such as metformin andphenformin; (b) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH₂); (c) sulfonylureas, such asacetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide;glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide;tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such asacarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose;pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR14,and the like; (e) cholesterol lowering agents such as (i) HMG-CoAreductase inhibitors (atorvastatin, itavastatin, fluvastatin,lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, andother statins), (ii) bile acid absorbers/sequestrants, such ascholestyramine, colestipol, dialkylaminoalkyl derivatives of across-linked dextran; Colestid®; LoCholest®, and the like, (ii)nicotinyl alcohol, nicotinic acid or a salt thereof, (iii)proliferator-activater receptor a agonists such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate),(iv) inhibitors of cholesterol absorption such as stanol esters,beta-sitosterol, sterol glycosides such as tiqueside; and azetidinonessuch as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate,ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; andother fibric acid derivatives, such as Atromid®, Lopid® and Tricor®, andthe like, and PPARα agonists as described in WO 97/36579; (g) PPARδagonists, such as those disclosed in WO97/28149; (h) PPAR α/δ agonists,such as muraglitazar, and the compounds disclosed in U.S. Pat. No.6,414,002; (i) anti-obesity agents, such as (1) growth hormonesecretagogues, growth hormone secretagogue receptoragonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686,CP-424,391, L-692,429, and L-163,255, and such as those disclosed inU.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3)cannabinoid receptor ligands, such as cannabinoid CB 1 receptorantagonists or inverse agonists, such as rimonabant, taranabant,AMT-251, and SR-14778 and SR141716A (Sanofi Synthelabo), SLV-319(Solvay), BAY 65-2520 (Bayer) and those disclosed in U.S. Pat. Nos.5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736,5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765,WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061,WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO 03/007887, WO04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, suchas fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5)β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda),CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreaticlipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267,lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferylphosphate, and those disclosed in PCT Application No. WO 01/77094; (7)neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304,LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8)neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X,GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A,CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, andthose disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354;6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332;6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and6,723,847, European Patent Nos. EP-01010691, and EP-01044970; and PCTInternational Patent Publication Nos. WO 97/19682, WO 97/20820, WO97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists,such as those disclosed in WO 01/21577 and WO 01/21169; (10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such asT-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO03/004027; (11) melanin-concentrating hormone 2 receptor (MCH2R)agonist/antagonists; (12) orexin receptor antagonists, such asSB-334867-A, and those disclosed in patent publications herein; (13)serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline; (14) melanocortin agonists, such as Melanotan II; (15) Mc4r(melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron),ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14(Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and thosedisclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19)CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and thosediscribed in U.S. Pat. No. 5,739,106; (21) GLP-1 agonists; (22)corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3)modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists,such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate,clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), andO-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) β-hydroxy steroiddehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase)inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil,amrinone, milrinone, cilostamide, rolipram, and cilomilast; (27)phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine)transport inhibitors, such as GW 320659, despiramine, talsupram, andnomifensine; (29) ghrelin receptor antagonists, such as those disclosedin PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin,including recombinant human leptin (PEG-OB, Hoffman La Roche) andrecombinant methionyl human leptin (Amgen); (31) leptin derivatives;(32) BRS3 (bombesin receptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron); (35) monoamine reuptakeinhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2,or 3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid; (37) thyroid hormone β agonists, such asKB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such asCerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoidantagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed indel Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44)dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucinethiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225,TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, sitagliptin;and the compounds disclosed in U.S. Pat. No. 6,699,871, WO 03/004498; WO03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; andWO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucosetransporter inhibitors; (48) phosphate transporter inhibitors; (49)Metformin (Glucophage®); (50) Topiramate (Topimax®); (50) peptide YY,PYY 3-36, peptide YY analogs, derivatives, and fragments such asBIM-43073D, BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci.44(3):643-48 (1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists suchNPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP), and other Y4 agonists such as1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib,valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522,ABT963, CS502 and GW406381; (55) Neuropeptide Y1 (NPY1) antagonists suchas BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56)Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone,naloxone, naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroiddehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and thosedisclosed in WO 01/90091, WO 01/90090, WO 01/90092, U.S. Pat. No.6,730,690 and US 2004-0133011; (58) aminorex; (59) amphechloral; (60)amphetamine; (61) benzphetamine; (62) chlorphentermine; (63)clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67)cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70)N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex;(74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77)levamfetamine; (78) levophacetoperane; (79) mefenorex; (80)metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83)pentorex; (84) phendimetrazine; (85) phenmetrazine; (86) picilorex; (87)phytopharm 57; and (88) zonisamide., (89) neuromedin U and analogs orderivatives thereof, (90) oxyntomodulin and analogs or derivativesthereof, and (91) Neurokinin-1 receptor antagonists (NK-1 antagonists)such as the compounds disclosed in: U.S. Pat. Nos. 5,162,339, 5,232,929,5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and5,637,699.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine andsertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline;moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone,trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam,chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam;buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceuticallyacceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with anti-Alzheimer's agents; beta-secretase inhibitors,such as verubecstat; gamma-secretase inhibitors; growth hormonesecretagogues; recombinant growth hormone; HMG-CoA reductase inhibitors;NSAID's including ibuprofen; vitamin E; anti-amyloid antibodies; CB-1receptor antagonists or CB-1 receptor inverse agonists; antibiotics suchas doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptorantagonists, such as memantine; cholinesterase inhibitors such asgalantamine, rivastigmine, donepezil, and tacrine; growth hormonesecretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin;histamine H₃ antagonists; AMPA agonists; PDE IV inhibitors; GABA_(A)inverse agonists; or neuronal nicotinic agonists.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate,clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof, and the like, or the subject compound may beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole.

In another embodiment, the subject compound may be employed incombination with acetophenazine, alentemol, benzhexol, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl,thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone.

In another embodiment, the subject compound may be employed incombination with a nicotine agonist or a nicotine receptor partialagonist such as varenicline, opioid antagonists (e.g., naltrexone(including naltrexone depot), antabuse, and nalmefene), dopaminergicagents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidatehydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g.,Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g.,Adderall®)) and anti-obesity agents, such as apo-B/MTP inhibitors,11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors,peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists,monoamine reuptake inhibitors, sympathomimetic agents, 33 adrenergicreceptor agonists, dopamine receptor agonists, melanocyte-stimulatinghormone receptor analogs, 5-HT2c receptor agonists, melaninconcentrating hormone receptor antagonists, leptin, leptin analogs,leptin receptor agonists, galanin receptor antagonists, lipaseinhibitors, bombesin receptor agonists, neuropeptide-Y receptorantagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, other orexin receptor antagonists, glucagon-like peptide-1receptor agonists, ciliary neurotrophic factors, human agouti-relatedprotein antagonists, ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, and neuromedin U receptor agonists, andpharmaceutically acceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with an anoretic agent such as aminorex, amphechloral,amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; selectiveserotonin reuptake inhibitor (SSRI); halogenated amphetaminederivatives, including chlorphentermine, cloforex, clortermine,dexfenfluramine, fenfluramine, picilorex and sibutramine; andpharmaceutically acceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with an opiate agonist, a lipoxygenase inhibitor, such as aninhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as acyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the subject compound may beadministered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention may beeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Pharmaceutical compositions of thepresent compounds may be in the form of a sterile injectable aqueous oroleagenous suspension. The compounds of the present invention may alsobe administered in the form of suppositories for rectal administration.For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention may be employed.The compounds of the present invention may also be formulated foradministered by inhalation. The compounds of the present invention mayalso be administered by a transdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art (e.g. PCT PatentPublications WO2001/68609, WO2004/085403, WO2005/118548, WO2008/147518,WO2009/143033 and WO2010/048012) or as illustrated herein. The followingabbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl;Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl; Boc: tert-butyloxycarbonyl; BSA: bovine serum albumin; CbzCl: benzylchloroformate; CDI:carbonyl diimidazole; DCM: dichloromethane; DCE: dichloroethane; DEAD:diethylazodicarboxylate; DIPEA: N,N-diisopropylethylamine; DMF:N,N-dimethylformamide; DMSO: dimethylsulfoxide; CH₂Cl₂: dichloromethane;EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; Et₃N:triethylamine; EtOAc: ethylacetate; EtOH: ethanol; HCl: hydrogenchloride; HATU: (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate); HOAt: 1-hydroxy-7-aza-benzotriazole; HOBT:hydroxybenzotriazole hydrate; HPLC: high performance liquidchromatography; Hunig's base: N,N-diisopropylethylamine; MeOH: methanol;MgSO₄: magnesium sulfate; MTBE: methyl tert-butyl ether; NaHCO₃: sodiumbicarbonate; NaOH: sodium hydroxide; NMM: N-methylmorpholine; PyClu:1-(chloro-1-pyrrolidinylmethylene)-pyrrolidinium hexafluorophosphate;rt: room temperature; SOCl₂: thionyl chloride; T3P:2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; THF:tetrahydrofuran; TFA: trifluoracetic acid. The compounds of the presentinvention can be prepared in a variety of fashions.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

INTERMEDIATES Intermediate A 2-(2,2-difluoroethoxy)benzoic acid

Step 1: 2,2-difluoroethyl 4-methylbenzenesulfonate (A1)

To a solution of compound 2,2-difluoroethanol (8.2 g, 100 mmol) in DCM(200 mL) at 0° C. was added Et₃N (15.1 g, 150 mmol) and TsCl (19.0 g,100 mmol). The resulting mixture was stirred at 0° C. for 0.5 h, thenpoured into water and extracted with DCM (200 mL×3). The combinedorganic layer was dried over MgSO₄, filtered and concentrated in vacuoto give the title compound (23.6 g, 100%) as colorless oil withoutfurther purification.

Step 2: methyl 2-(2,2-difluoroethoxy)benzoate (A2)

To a suspension of the product from step 1 (7.6 g, 50.0 mmol) and K₂CO₃(13.8 g, 100 mmol) in THF (300 mL) was added methyl 2-hydroxybenzoate(11.8 g, 50.0 mmol). The resulting mixture was stirred at 70° C.overnight. After cooled to RT, the mixture was poured into water andextracted with EtOAc (200 mL×3). The combined organic layer was driedover MgSO4, filtered and concentrated in vacuo. The residue was purifiedby chromatography on silical gel (3.2% EtOAc in petroleum ether) to givethe title compound.

Step 3: 2-(2,2-difluoroethoxy)benzoic acid (Intermediate A)

To a solution of the product from step 2 (4.5 g, 20.8 mmol) inmethanol/water (100 mL/100 mL) was added LiOH.H2O (4.37 g, 104 mmol).The resulting mixture was stirred at RT overnight. The mixture wasdiluted with water (100 mL) and extracted with EtOAc (100 mL×3). Theaqueous layer was acidified with HCl (2 mol/L) to pH=2 and extractedwith DCM (100 mL×4). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuoto give the title compound as a solid. LRMS m/z (M+H) 203.1 found, 203.1required.

Intermediate B 2-(2,2,2-trifluoroethyl)benzoic acid

Step 1: methyl 2-formylbenzoate (B1)

To a solution of H₂SO₄ (2 mL) in MeOH (100 mL) was added 2-formylbenzoic acid (10.0 g, 66.2 mmol). The resulting mixture was stirred at70° C. overnight. After cooled to RT, the mixture was concentrated invacuo, adjusted pH to 8 with aq. NaHCO₃ and extracted with EtOAc (10mL×3). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel gradient chromatography (10% EtOAc in petroleum ether) to give thetitle compound as sm oil. LRMS m/z (M+H) 165.1 found, 165.1 required

Step 2: methyl 2-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (B2)

To a suspension of the compound from step 1 (3.60 g, 21.9 mmol) and CsF(1.67 g, 10.9 mmol) in dry THF (36 mL) at 0° C. was added TMSCF₃ (4.68g, 32.9 mmol). The mixture was stirred at 0° C. for 1 h. The mixture wasadjusted to pH=2 with 1N HCl solution and stirred for another 1 h andextracted with EtOAc (10 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo and theresidue was purified by silica gel gradient chromatography (10% EtOAc inpetroleum ether) to give the title compound as an oil. LRMS m/z (M+H)235.1 found, 235.1 required.

Step 3: methyl 2-(2,2,2-trifluoro-1-((methylsulfonal)oxy)ethyl)benzoate(B3)

To a solution of the compound from step 2 (1.10 g, 4.70 mmol) and TEA(1.96 mL, 14.1 mmol) in DCM (10 mL) at RT was added MsCl (807 mg, 7.05mmol) dropwise. The resulting mixture was stirred at RT for 1.5 hr,diluted with DCM and washed with brine (5 mL×2), dried over anhydrousNa₂SO₄, filtered and the filtrate was concentrated in vacuo to give thetitle compound as a solid. LRMS m/z (M+H) 313.0 found, 313.0 required.

Step 4: methyl 2-(2,2,2-trifluoroethyl)benzoate (B4)

A solution of the product from step 3 (1.00 g, 3.20 mmol) in methanol(40 mL) was stirred in the presence of Pd/C (1.0 g) under 50 psi of H₂atmosphere at 50° C. overnight. LCMS indicated the reaction wascompleted, the mixture was filtered through celite pad. The filtrate wasconcentrated in vacuo to give the title compound as an oil. LRMS m/z(M+H) 219.1 found, 219.1 required.

Step 5: 2-(2,2,2-trifluoroethyl)benzoic acid (Intermediate B)

To a solution of the product from step 4 (550 mg, 2.50 mmol) in MeOH/H₂O(10 mL/1 mL) was added LiOH (240 mg, 10.0 mmol) at RT. The resultingmixture was stirred at RT for 12 hours. Water (10 mL) was added and themixture was washed with EtOAc (10 mL×2) and adjusted pH=˜3 with conc.HCland extracted with DCM (20 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and the filtratewas concentrated in vacuo to give the title compound as a solid. LRMSm/z (M+H) 205.0 found, 205.0 required.

Intermediate C 2-(2,2-difluoroethyl)benzoic acid

Step 1: ethyl 2-formylbenzoate (C1)

To a suspension of 2-formylbenzoic acid (34.5 g, 0.23 mol) and K₂CO₃(65.1 g, 0.47 mol) in acetone (500 mL) was added EtI (72 g, 0.46 mol).The resulting mixture was stirred at 70° C. overnight. After cooled toRT, the mixture was filtered and the filtrate was concentrated in vacuoto give the title compound as an oil which was used without furtherpurification. LRMS m/z (M+H) 179.2 found, 179.2 required.

Step 2: ethyl 2-(2,2-difluorovinyl)benzoate (C2)

To a stirred solution of the compound from step 1 (20.0 g, 0.11 mol) inDMF (190 mL) was added F₂ClCCO₂Na (25.6 g, 0.17 mol) and PPh₃ (44.2 g,0.17 mol). The resulting mixture was stirred at 120° C. overnight. Aftercooled to RT, the mixture was diluted with water (200 mL) and extractedwith EtOAc (300 mL×2). The combined organic layer was washed with brine(300 mL×2), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel gradient chromatography (0%-10% EtOAcin petroleum ether) to give the title pure product as an oil and thecrude product (50% HPLC purity, 25 g, containing triphenylphosphineoxide) as an oil. LRMS m/z (M+H) 213.2 found, 213.2 required.

Step 3: ethyl 2-(2,2-difluoroethyl)benzoate (C3)

To a stirred solution of the product from step 2 (2.7 g, 13 mmol) inEtOH (80 mL) was added Pd/C (0.4 g). The resulting mixture was stirredat 50° C. under hydrogen atmosphere (50 psi) overnight. After cooled toRT, the mixture was filtered and the filtrated was concentrated in vacuoto give the title compound as an oil. LRMS m/z (M+H) 215.2 found, 215.2required.

Step 4: 2-(2,2-difluoroethyl)benzoic acid (Intermediate C)

To a solution of the product from step 3 (2.7 g, 12.6 mmol) in THF/H₂O(20 mL/7 mL) was added LiOH.H₂O (1.06 g, 25.2 mmol). The resultingmixture was stirred at RT overnight. After the solvent was removed, theresidue was diluted with water (20 mL) and extracted with EtOAc(20mL×3). The aqueous layer was adjusted to pH=3, the precipitated wascollected via filtration to give the title compound as a solid.

Intermediate D 2-(2,2,2-trifluoroethyl)nicotinic acid

Step 1: 2-(2,2-difluoroethyl)benzoic acid (D1)

To a solution of 2,3-dibromopyridine (10 g, 42.2 mmol) in toluene (100mL) was dropwise added n-BuLi (20.26 mL, 50.7 mmol) at −78° C. under N₂.After the resulting mixture was stirred at −78° C. for 2 h, DMF (3.92mL, 50.7 mmol) was added dropwise. The mixture was stirred at −78° C.for another 2 h. TLC (50% EtOAc in petroleum ether) indicated thereaction was finished. The mixture was quenched with water at −78° C.and extracted with EtOAc (300 mL×3). The combined organic layers weredried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified by combiflash (25% EtOAc in petroleum ether) to give the titlecompound as yellow oil. LRMS m/z (M+H) 186.1 found, 186.1 required.

Step 2: 2-(2,2-difluoroethyl)benzoic acid (D2)

To a suspension of the product from step 1 (3.5 g, 18.9 mmol) and CsF(4.3 g, 28.4 mmol) in THF (30 mL) at 0° C. was added TMSCF₃ (4.0 g, 28.4mmol) under N₂. The resulting mixture was allowed to be stirred at roomtemperature for 2 h. LC-MS indicated the reaction was finished. Themixture was diluted with water and extracted with EtOAc (100 mL×3). Theorganic layers were combined and dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by combiflash (25% EtOAcin petroleum ether) to give the title compound as an oil. LRMS m/z (M+H)256.1 found, 256.1 required.

Step 3: 2-(2,2-difluoroethyl)benzoic acid (D3)

To a solution of the product from step 2 (1.8 g, 7 mmol) and DIPEA (1.8g, 14 mmol) in DCM (10 mL) was dropwise added MsCl (1.1 mL, 14 mmol) at0° C. under N₂. The mixture was stirred at 0° C. for 2 h. TLC (25% EtOAcin petroleum ether) indicated the reaction was finished. The mixture wasdiluted with water, extracted with EtOAc (200 ml×3). The organic layerswere combined, dried over MgSO4, filtered and concentrated in vacuo togive the title compound as an oil. LRMS m/z (M+H) 334.3 found, 334.3required.

Step 4: 2-(2,2-difluoroethyl)benzoic acid (D4)

A mixture of the product from step 3 (1.0 g, 3 mmol), Pd(dppf)Cl₂ (100mg), TEA (909 mg, 9 mmol) in methanol (30 mL) was stirred at 120° C. for16 hs under CO (3 MPa). LC-MS indicated the reaction was finished. Afterfiltration, the filtrate was concentrated in vacuo. The residue waspurified by silica chromatography (25% EtOAc petroleum ether) to givethe crude title compound as an oil. LRMS m/z (M+H) 220.1 found, 220.1required.

Step 5: 2-(2,2-difluoroethyl)benzoic acid (Intermediate D)

To a solution of the product from step 4 (1.0 g, 4.6 mmol) in themixture of MeOH (15 ml) and water (15.00 mL) was added LiOH (0.22 g, 9.1mmol). The resulting mixture was stirred at room temperature for 2 h.After most of MeOH was removed under reduced pressure, the residue wasdiluted with water (20 mL) and extracted with EtOAc (100 mL×3). Theaqueous layer was adjusted pH=˜1 with conc. HCl and then extracted withEtOAc (100 ml×3). The organic layers were combined, dried over MgSO₄,filtered and concentrated in vacuo to give the title compound as asolid. LRMS m/z (M+H) 206.1 found, 206.1 required.

Intermediate E 2-propylbenzoic acid

Step 1: 2-propylbenzoic acid (Intermediate E)

To a solution of 2-methylbenzoic acid (20 g, 0.15 mmol) in THF (200 mL)was dropwise added s-BuLi (340 mL, 0.45 mmol) at −78° C. After addition,the mixture was stirred at −78° C. for 0.5 h. Then iodoethane (137 g,0.88 mmol) was added. The resulting mixture was allowed to warm up to RTand stirred overnight, quenched with water and extracted with EtOAc (300mL×3). The combined organic layers were washed with brine, dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified bysilica chromatography (50% EtOAc in petroleum ether) to give the titlecompound as an oil. LRMS m/z (M+H) 165.1 found, 165.1 required.

Intermediate F 3-(2H-1,2,3-triazol-2-yl)picolinic acid

Step 1: 3-(2H-1,2,3-triazol-2-yl)picolinic acid (Intermediate F)

To a solution of 3-bromonicotinic acid (1.4 g, 6.93 mmol) in DMSO (14mL) was added 2H-1,2,3-triazole (0.718 g, 10.40 mmol), cesium carbonate(4.74 g, 14.55 mmol), copper(I) iodide (0.132 g, 0.693 mmol), andN1,N2-dimethylcyclohexane-1,2-diamine (0.099 g, 0.693 mmol) and thereaction mixture sparged with nitrogen and stirred at 120° C. overnight.The cooled reaction mixture was diluted with 1 N NaOH (15 mL) and washedwith EtOAc (15 mL). The aqueous layer was acidified with 12 N HCl andextracted with EtOAc (4×20 mL). The combined organic layers were washedwith brine, dried over NaSO₄, filtered, and the solvent was evaporatedin vacuo. The crude product was purified by chromatography on silica(0-100% (EtOAc: 5% AcOH in EtOAc). The purified fractions were combinedand azeotroped with toluene (3×100 mL) to give3-(2H-1,2,3-triazol-2-yl)picolinic acid as a solid. LSMS m/z (M+H)191.05 found, 191.05 required.

Intermediate G 2-(1H-Pyrazol-1-yl)nicotinic acid

Step 1: 2-(1H-Pyrazol-1-yl)nicotinic acid (Intermediate G)

To a solution of 2-bromonicotinic acid (1.4 g, 6.93 mmol) in DMSO (14mL) was added 1H-pyrazole (0.707 g, 10.40 mmol), cesium carbonate (4.74g, 14.55 mmol), copper(I) iodide (0.132 g, 0.693 mmol), andN1,N2-dimethylcyclohexane-1,2-diamine (0.099 g, 0.693 mmol). The mixturewas sparged with nitrogen and heated at 120° C. overnight. The cooledreaction mixture was diluted with 1 N NaOH (15 mL) and washed with EtOAc(15 mL). The aqueous layer was acidified with 12 N HCl and extractedwith EtOAc (4×20 mL). The combined organic layers were washed withbrine, dried over NaSO₄, filtered, and the solvent was evaporated invacuo. The crude material was purified by silica gel gradientchromatography [0-100% (5% AcOH in EtOAc)/hexanes]. The purifiedfractions were combined and azeotroped with toluene (3×100 mL) to give2-(1H-pyrazol-1-yl)nicotinic acid as a solid. LSMS m/z (M+H) found,required.

Intermediate H 3-(1H-Pyrazol-1-yl)pyrazine-2-carboxylic acid

Step 1: 3-(1H-Pyrazol-1-yl)pyrazine-2-carboxylic acid (Intermediate H)

To a suspension of sodium hydride (278 mg, 6.95 mmol, 60% in oil) in DMF(10 mL) was added 1H-pyrazole (279 mg, 4.11 mmol) at RT and theresulting mixture stirred at room temperature for 30 mins.3-Chloropyrazine-2-carboxylic acid (500 mg, 3.16 mmol) was added and themixture heated to 60° C. for 2 h. After cooling to RT, water (20 mL) wasadded and the mixture extracted with 4.7% MeOH in DCM (20 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound as asolid. LRMS m/z (M+H) 191.0 found, 191.0 required.

Intermediate I 3-(Pyridin-2-yl)pyrazine-2-carboxylic acid

Step 1: methyl 3-chloropyrazine-2-carboxylate (I1)

To a solution of 3-chloropyrazine-2-carboxylic acid (100 mg, 0.63 mmol)in DCM/MeOH (2 mL: 0.2 mL) was added TMSCHN₂ (0.47 mL, 0.95 mmol) at RTand the resulting mixture stirred at RT for 2 h. Acetic acid (0.2 mL)was added and the mixture diluted with water (2 mL) and extracted withDCM (4 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound as a oil. LRMS m/z (M+H) 173.0 found, 173.0 required.

Step 2: Methyl 3-(pyridin-2-yl)pyrazine-2-carboxylate (I2)

To a solution of the product from step 1 (100 mg, 0.58 mmol) in toluene(2 mL) was added Pd(PPh₃)₄ (134 mg, 0.12 mmol) and2-(tributylstannyl)pyridine (213 mg, 0.58 mmol) at room temperature andthe resulting mixture heated to 100° C. overnight. After cooling to RT,the mixture was filtered and 5 mL of aq. KF solution was added to thefiltrate. The resulting mixture was stirred for 30 mins and extractedwith EtOAc (5 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography (30% EtOAc in petroleum ether) to provide thetitle compound as a oil. LRMS m/z (M+H) 216.1 found, 216.1 required.

Step 3: 3-(Pyridine-2-yl)pyrazine-2-carboxylic acid (Intermediate I)

A solution of the product from step 2 (50 mg, 0.23 mmol) and NaOH (27.8mg, 0.69 mmol) in 2 mL of methanol and 0.1 mL of water was stirred at RTovernight. After adjusting to pH=5 with 1N HCl, the mixture wasconcentrated in vacuo. The residue was dissolved in EtOAc (8 mL),stirred for 10 mins and filtered. The filtrate was concentrated invacuum to give the title compound as a solid. LRMS m/z (M+H) 202.1found, 202.1 required.

Intermediate J 2-(2H-Tetrazol-2-yl)benzoic acid

To a 20 mL microwave tube was charged 2-iodobenzoic acid (1.85 g, 7.46mmol), cesium carbonate (4.06 g, 12.5 mmol), copper(I) iodide (0.128 g,0.671 mmol), and DMA (8.0 mL). N,N′-Dimethylglyine (0.131 g, 1.27 mmol)and tetrazole (1.29 g, 18.4 mmol) were added, and the solutionirradiated in a microwave reactor at 100° C. for 1 hour. The reactionmixture was diluted with water and 1 N aqueous sodium hydroxide andwashed with EtOAc. The aqueous fraction was acidified with conc. HCl andextracted 2× with EtOAc. The combined organic fractions were washed withbrine, dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography [0-85% (1% acetic acidin EtOAc) in hexanes], to provide the title compound.

Intermediate K 4-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid

To a mixture of 2-bromo-4-fluorobenzoic acid (30 g, 137 mmol), cesiumcarbonate (89.26 g, 274 mmol) and CuI (5.27 g, 27.4 mmol) in DMF (200mL) were added N,N′-dimethylcyclohexane-1,2-diamine (3.7 mL, 23.3 mmol)and 1H-1,2,3-triazole (18.92 g, 274 mmol). The resulting mixture wasstirred at 110° C. overnight, cooled, concentrated in vacuo and dilutedwith water (150 mL). The aqueous layer was extracted with EtOAc (300mL×3). The aqueous layer was acidified with 2N HCl and extracted withEtOAc (300 mL×4). The combined organic layers were washed with brine(150 mL×3), dried over Na₂SO₄, filtered and the filtrate concentrated invacuo. The residue was purified by chromatography on silica gel(petroleum ether:EtOAc=100:1˜5:1) to provide the title compound as asolid. LRMS m/z (M+H) 208.0 found, 208.0 required.

Intermediate L 2-(2,2-Difluoroethoxy)nicotinic acid

To a suspension of 2,2-difluoroethanol (492 mg, 6.0 mmol) in DMF (10 mL)at 0° C. was added NaH (180 mg, 4.5 mmol), and the mixture stirred at 0°C. for 0.5 h. A suspension of 2-fluoronicotinic acid (423 mg, 3.0 mmol)and NaH (180 mg, 4.5 mmol) in DMF (5 mL) was added dropwise at 0° C. andthe resulting mixture stirred at RT overnight. The mixture was dilutedwith water, acidified to pH-3 with IM HCl and extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overMgSO₄, filtered, and concentrated in vacuo to give the crude productwhich was used directly without any further purification. LRMS m/z (M+H)204.1 found, 204.0 required.

Intermediate M 2-(2,2,2-trifluoroethoxy)nicotinic acid

To a suspension of 2,2,2-trifluoroethanol (600 mg, 6.0 mmol) in DMF (10mL) was added NaH (180 mg, 4.5 mmol) at 0° C., and the mixture wasstirred at 0° C. for 0.5 h. A suspension of 2-fluoronicotinic acid (423mg, 3.0 mmol) and NaH (180 mg, 4.5 mmol) in DMF (5 mL) was addeddropwise at 0° C. The resulting mixture was stirred at rt. overnight.The mixture was diluted with water and acidified to pH-3 with IM HCl andextracted with EtOAc (30 mL×3). The organic layers were combined, washedwith brine, dried over magnesium sulfate, filtered, and concentrated invacuo to give the crude title compound which was used directly withoutany further purification. LRMS m/z (M+H) 222.0 found, 222.0 required.

Intermediate N 2-(2,2-difluorocyclopropyl)benzoic acid

Step 1: methyl 2-vinylbenzoate (N)

To a solution of methyl 2-bromobenzoate (1.2 g, 5.5 mmol) indioxane/water (15 mL/0.6 mL) were added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.7 g, 11.1 mmol),K₂CO₃ (1.53 g, 11.1 mmol) and Pd(dppf)Cl₂ (0.4 g). The resulting mixturewas stirred at 100° C. for overnight. The mixture was diluted with water(20 mL) and extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo. The crude product was purified by Prep-TLC(petroleum ether:EtOAc=10:1) to give the title compound as oil.

Step 2: methyl 2-(2,2-difluorocyclopropyl)benzoate (N2)

The mixture of the product from step 1 (500 mg, 3.09 mmol) and KI (1.15g, 6.94 mmol) in DME (27.8 mg, 0.31 mmol) and dioxane (461.7 mg, 5.25mmol) was stirred at 120° C. for 5 minutes. Then TMSCl (666.6 mg, 6.17mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.2 g, 6.17mmol) was added to the mixture and the mixture was stirred at sametemperature for 24 hs. LC-MS indicated the starting material was totallyconverted to the product. The mixture was diluted with water and EtOAc.The mixture was extracted with EtOAc (10 mL×3). The organic layers werecombined, dried over Na₂SO₄ and filtered. The organic phase wasconcentrated under reduced pressure to afford the crude product whichwas purified through Prep-HPLC to afford the target product as a solid.LRMS m/z (M+H) 213.1 found, 213.2 required.

Step 3: 2-(2,2-difluorocyclopropyl)benzoic acid (Intermediate N)

A solution of the product from step 1 (170 mg, 0.8 mmol) and LiOH.H2O(23 mg, 0.55 mmol) in THF: H2O:MeOH (2:2:1) was stirred at 0° C.overnight. The reaction mixture was quenched by H₂O (6 mL), thenadjusted pH to 2 with 1 M HCl, extracted with EtOAc (8 mL×3). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄. After filtration, the filtrate was concentrated in vacuo and theresidue was purified by Prep-HPLC to give the title compound as solid.LRMS m/z (M+H) 199.0 found, 199.2 required.

Intermediate O 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid

Step 1: 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile (O1)

A solution of 2-fluoro-5-methylbenzonitrile (10 g, 74.0 mmol),2H-1,2,3-triazole (5.11 g, 74.0 mmol) and K₂CO₃ (20.4 g, 148.0 mmol) inDMF (100 mL) was stirred at 90° C. overnight. After cooled to rt., brine(80 mL) was added to dilute the reaction and the mixture was extractedwith ethyl acetate (80 mL×3). The combined organic layer was dried withNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bychromatography column (9.1% EtOAc in petroleum ether) to give the titlecompound as a solid. LRMS m/z (M+H) 185.1 found, 185.1 required.

Step 2: 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate O)

A mixture of the product from step 1 (3.3 g, 18.0 mmol) in 2 M NaOH (30mL) was refluxed overnight. After cooled to rt., the mixture wasadjusted the pH to 1-2 with 2 N HCl and extracted with ethyl acetate (50mL×3). The combined organic layer was washed with brine (50 mL×3), driedover Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound as a solid. LRMS m/z (M+H) 204.1 found, 204.1 required.

Example 1

(R)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanoneStep 1: benzyl 2-(2-hydroxyethyl)piperidine-1-carboxylate (1)

To a solution of 2-(piperidin-2-yl)ethanol (20.0 g, 154.8 mmol) in EtOAc(200 mL) was added CbzCl (26.4 g, 154.8 mmol) and saturated aq. NaHCO₃(200 mL). The resulting mixture was stirred at RT overnight, thendiluted with water (200 mL) and extracted with EtOAc (200 mL×3). Thecombined organic layers were washed with brine (200 mL×3), dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound asan oil, which was used in the next step without further purification.LRMS m/z (M+H) 264.1 found, 264.2 required.

Step 2: 2-(1-((benzyloxy)carbonyl)piperidin-2-yl)acetic acid (2)

To a solution of the product from step 1 (40 g, 151.9 mmol) in CH₃CN(300 mL) was added a solution of Na₂HPO₄ in 181.3 mL of water and TEMPO(3.96 g, 25.3 mmol). Then a solution of NaClO₂ (27.48 g, 303.8 mmol) inwater (300 mL) and aq. NaClO (37.1 mL, 6-7 w %) was addedsimultaneously. The resulting mixture was stirred at 35° C. overnight.The organic solvent was concentrated in vacuo. The water layer wasdiluted with water (200 mL), adjusted pH to 10 with 2 M NaOH, andextracted with EtOAc (200 mL×3). The aqueous layer was adjusted pH to 4with 2 M HCl and extracted with EtOAc (200 mL×3). The combined organiclayers were washed with brine (150 mL×3), dried over Na₂SO₄, filteredand the filtrate was concentrated in vacuo. The residue was purified bychromatography column (50% EtOAc in petroleum ether) to give the titlecompound as an oil. LRMS m/z (M+H) 278.1 found, 278.1 required.

Step 3: benzyl2-(2-((1-methoxy-1,3-dioxobutan-2-yl)amino)-2-oxoethyl)piperidine-1-carboxylate(3)

To a solution of the product from step 2 (33.5 g, 120.8 mmol) in DCM(500 mL) was added HATU (55.1 g, 144.9 mmol) and methyl2-amino-3-oxobutanoate hydrochloride (28.3 g, 169.1 mmol) at RT. Themixture was stirred at RT for 30 mins, and TEA (67.3 mL) was addedslowly. The mixture was stirred at RT overnight. The mixture was dilutedwith DCM, washed with NaHCO₃ (300 mL×3) and brine (300 mL×3), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bychromatography column (5% EtOAc in DCM) to give the title compound as anoil. LRMS m/z (M+H) 391.1 found, 391.2 required.

Step 4: methyl2-((1-((benzyloxy)carbonyl)piperidin-2-yl)methyl)-5-methyloxazole-4-carboxylate(4)

To a solution of I₂ (27.0 g, 106.5 mmol), PPh3 (27.9 g, 106.5 mmol) andTEA (29.7 mL, 213.1 mmol) in DCM (250 mL) was added a solution of theproduct from step 3 (20.8 g, 53.2 mmol) in DCM (200 mL). The resultingmixture was stirred at RT overnight, then poured into water andextracted with DCM (300 mL×3). The combined organic layers were washedwith brine (300 mL×3), dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by combiflash (66% EtOAc in petroleumether) to give the title compound as an oil. LRMS m/z (M+H) 373.1 found,373.2 required.

Step 5: benzyl2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidine-1-carboxylate(5)

To a solution of MeMgBr (53.6 mL, 161.0 mmol, 3 M in ether) was added asolution of the product from step 4 (7.0 g, 18.7 mmol) in THF (70 mL)dropwise at 0° C. The mixture was stirred at 0° C. for 3 h, thenquenched with aq. NH₄Cl (50 mL), and extracted with EtOAc (50 mL×3). Thecombined organic layer was washed with brine (50 mL×3), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (20% EtOAc in petroleum ether) to give the titlecompound as an oil. LRMS m/z (M+H) 373.1 found, 373.2 required.

Step 6: 2-(5-methyl-2-(piperidin-2-ylmethyl)oxazol-4-yl)propan-2-ol (6)

To a solution of the product from step 5 (5.8 g, 15.5 mol) in MeOH (80mL) was added Pd/C (600 mg, 10 w %) at RT. The mixture was stirred at RTovernight under H₂ atmospheres (1 atm). The mixture was filtered and thefiltrate was concentrated in vacuo to give the title compound as an oil.LRMS m/z (M+H) 239.1 found, 239.2 required.

Step 7: (R)-2-(5-methyl-2-(piperidin-2-ylmethyl)oxazol-4-yl)propan-2-ol(7)

The product from step 6 (3.6 g) was separated by SFC (Chiralpak IC250×30 mm I.D., 10 um, CO2/ETOH (0.1%) NH₃.H2O=65/35 at 200 mL/min) togive the title compound (the slower eluting isomer in SFC).

Step 8:(R)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone

A mixture of 2-(2H-1,2,3-triazol-2-yl)benzoic acid (285 mg, 1.5 mmol) inSOCl₂ (3 mL) was stirred at RT for 0.5 h. Then the mixture wasconcentrated in vacuo. To a solution of the product from step 7 (300 mg,1.26 mmol) and TEA (0.5 mL, 3.78 mmol) in DCM (3 mL) was added the aboveresidue dropwise at 0° C. The mixture was stirred at 0° C. for 2 h.water (2 mL) was added to quench the reaction and the mixture wasextracted with DCM (3 mL×3). The combined organic layers was washed withbrine (3 mL×3), dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by Prep-HPLC to give the title compound as asolid. LRMS m/z (M+H) 410.1 found, 410.2 required.

Example 2

(R)-(2-ethoxypyridin-3-yl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone

To a solution of compound 7 (Example 1, Step 7) (30.0 mg, 0.13 mmol) inDMF (1 mL) was added HATU (57.0 mg, 0.15 mmol), 2-ethoxynicotinic acid(25.2 mg, 0.15 mmol) and TEA (32.0 mg, 0.30 mmol). The mixture wasstirred at RT overnight. Then the mixture was purified by Prep-HPLC togive the title compound as a solid. LRMS m/z (M+H) 388.2 found, 388.2required.

TABLE 1 The following compounds were prepared according to Example 2 andthe procedures herein. The starting materials are either commerciallyavailable or may be prepared as described in the synthesis ofintermediates, or may be prepared from commercially available reagentsusing conventional reactions well known in the art. LRMS ExampleStructure Name (M + H⁺) 3

(R)-(2-cyclopropylphenyl)(2- ((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2- yl)methyl)piperidin-1- yl)methanone Calc'd 383.2, found383.2 4

(R)-(4-fluoro-2-(2H-1,2,3- triazol-2-yl)phenyl)(2-((4-(2-hydroxypropan-2-yl)-5- methyloxazol-2- yl)methyl)piperidin-1-yl)methanone Calc'd 428.2, found 428.1 5

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2- (2,2,2-trifluoroethoxy)pyridin-3-yl)methanone Calc'd 442.2, found 442.2 6

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2- isopropoxypyridin-3- yl)methanone Calc'd402.2, found 402.2 7

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2- (pyrrolidin-1- yl)phenyl)methanone Calc'd412.2, found 412.2 8

(R)-(2-ethoxyphenyl)(2-((4-(2- hydroxypropan-2-yl)-5- methyloxazol-2-yl)methyl)piperidin-1- yl)methanone Calc'd 387.2, found 387.2 9

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2- (trifluoromethoxy)phenyl) methanone Calc'd427.2, found 427.2 10

(R)-(2-(1H-pyrazol-1- yl)phenyl)(2-((4-(2- hydroxypropan-2-yl)-5-methyloxazol-2- yl)methyl)piperidin-1- yl)methanone Calc'd 409.2, found409.2 11

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2- (2,2,2-trifluoroethyl)pyridin-3-yl)methanone Calc'd 426.2, found 426.2 12

(R)-(2-(2,2- difluoroethyl)phenyl)(2-((4-(2- hydroxypropan-2-yl)-5-methyloxazol-2- yl)methyl)piperidin-1- yl)methanone Calc'd 407.1, found407.2 13

(R)-(2-(1H-pyrazol-1- yl)pyridin-3-yl)(2-((4-(2- hydroxypropan-2-yl)-5-methyloxazol-2- yl)methyl)piperidin-1- yl)methanone Calc'd 410.2, found410.2 14

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2- phenylpyridin-3-yl)methanone Calc'd 420.2,found 420.2 15

(R)-(2- (difluoromethoxy)phenyl)(2- ((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2- yl)methyl)piperidin-1- yl)methanone Calc'd 409.2, found409.1 16

(R)-(2-(2,2- difluoroethoxy)pyridin-3-yl)(2-((4-(2-hydroxypropan-2-yl)-5- methyloxazol-2- yl)methyl)piperidin-1-yl)methanone Calc'd 424.2, found 424.2 17

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2- (2,2,2- trifluoroethoxy)phenyl)methanoneCalc'd 441.2, found 441.1 18

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2- (2,2,2-trifluoroethyl)phenyl)- methanoneCalc'd 425.2, found 425.1 19

(R)-(2-cyclopropyl-6- methoxypyridin-3-yl)(2-((4-(2-hydroxypropan-2-yl)-5- methyloxazol-2- yl)methyl)piperidin-1-yl)methanone Calc'd 414.2, found 414.2 20

(R)-(2-(2,2- difluoroethoxy)phenyl)(2-((4- (2-hydroxypropan-2-yl)-5-methyloxazol-2- yl)methyl)piperidin-1- yl)methanone Calc'd 423.2, found423.1 21

(R)-(3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)(2-((4-(2-hydroxypropan-2-yl)-5- methyloxazol-2- yl)methyl)piperidin-1-yl)methanone Calc'd 411.2, found 411.1 22

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(3- (pyridin-2-yl)pyrazin-2- yl)methanoneCalc'd 422.2, found 422.2 23

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(3- (pyrrolidin-1-yl)pyrazin-2- yl)methanoneCalc'd 414.2, found 414.2 24

(R)-(2-cyclobutylphenyl)(2-((4- (2-hydroxypropan-2-yl)-5-methyloxazol-2- yl)methyl)piperidin-1- yl)methanone Calc'd 397.2, found397.2 25

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(3- phenylpyridin-2-yl)methanone Calc'd 420.2,found 420.2 26

(R)-(3-(1H-pyrazol-1- yl)pyrazin-2-yl)(2-((4-(2- hydroxypropan-2-yl)-5-methyloxazol-2- yl)methyl)piperidin-1- yl)methanone Calc'd 411.2, found411.2 27

(2-(2,2- difluorocyclopropyl)phenyl)((R)- 2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2- yl)methyl)piperidin-1- yl)methanone Calc'd 419.2,found 419.1 28

(R)-(2-(2H-tetrazol-2- yl)phenyl)(2-((4-(2- hydroxypropan-2-yl)-5-methyloxazol-2- yl)methyl)piperidin-1- yl)methanone Calc'd 411.2, found411.2 29

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2- propylphenyl)methanone Calc'd 385.2, found385.2 30

(R)-(2-((4-(2-hydroxypropan-2- yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(5- methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone Calc'd 424.2, found 424.2

Example 31

(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2-(pyrimidin-2-yl)phenyl)methanone

To a mixture of compound 7 (Example 1, Step 7) (30.0 mg, 0.13 mmol),2-(pyrimidin-2-yl)benzaldehyde (27.8 mg, 0.151 mmol) and TEA (32.0 mg,0.300 mmol) was added T₃P (0.3 mL) at 0° C. The mixture was heated to50° C. for 16 h. After cooled to RT, the mixture was quenched with water(1 mL), and concentrated in vacuo. The residue was purified withPrep-HPLC to give the title compound as an oil. LRMS m/z (M+H) 421.2found, 421.2 required.

TABLE 2 The following table shows representative data for the compoundsof the Examples as orexin receptor antagonists as determined by theassays described herein. hOX2R FLIPR hOX1R FLIPR Example IC₅₀ (nM) IC₅₀(nM) 1 14 18 2 20 152 3 17 212 4 25 39 5 19 162 6 36 223 7 51 67 8 28256 9 109 348 10 51 129 11 1470 >10000 12 98 2182 13 24 51 14 38 80 1598 1093 16 49 373 17 99 952 18 118 1687 19 503 2307 20 112 690 21 2251850 22 558 2929 23 >10000 >10000 24 114 184 25 127 240 26 186 1412 2738 473 28 152 486 29 106 794 30 46 50 31 47 76

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

What is claimed is:
 1. A compound of the formula I:

wherein: A is selected from the group consisting of phenyl, naphthyl andheteroaryl; each of R^(1a), R^(1b) and R^(1c) is independently selectedfrom the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl,(4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1 (whereinif m is 0 or n is 0, a bond is present) and where the alkyl isunsubstituted or substituted with one to three substituentsindependently selected from R⁴, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl,where the cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from R⁴, (6) —(C═O)_(m)—C₂₋₄alkenyl, where thealkenyl is unsubstituted or substituted with one to three substituentsindependently selected from R⁴, (7) —(C═O)_(m)—C₂₋₄alkynyl, where thealkynyl is unsubstituted or substituted with one to three substituentsindependently selected from R⁴, (8) —(C═O)_(m)—O_(n)-phenyl or—(C═O)_(m)—O_(n)-naphthyl, where the phenyl or naphthyl is unsubstitutedor independently substituted with one to three substituentsindependently selected from R⁴, (9) —(C═O)_(m)—O_(n)-heterocycle, wherethe heterocycle is unsubstituted or substituted with one to threesubstituents independently selected from R⁴, (10) —(C═O)_(m)—NR¹⁰R¹¹,wherein R¹⁰ and R¹¹ are independently selected from the group consistingof: (a) hydrogen, (b) C₁₋₆alkyl, which is unsubstituted or substitutedwith R⁴, (c) C₃₋₆alkenyl, which is unsubstituted or substituted with R⁴,(d) C₃₋₆alkynyl, which is unsubstituted or substituted with R⁴, (e)C₃₋₆cycloalkyl which is unsubstituted or substituted with R⁴, (f)phenyl, which is unsubstituted or substituted with R⁴, and (g)heterocycle, which is unsubstituted or substituted with R⁴, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹²is selected from the definitions of R¹⁰ and R¹¹, (13) —CO₂H, (14) —CN,and (15) —NO₂; R⁴ is selected from the group consisting of: (1)hydroxyl, (2) halogen, (3) C₁₋₆alkyl, (4) —C₃₋₆cycloalkyl, (5)—O—C₁₋₆alkyl, (6) —O(C═O)—C₁₋₆alkyl, (7) —NH₂, (8) —NH—C₁₋₆alkyl, (9)—NO₂, (10) phenyl, (11) heterocycle, (12) —CO₂H, and (13) —CN; R⁵ isselected from the group consisting of: (1) hydrogen, (2) halogen, (3)C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl,—O—C₁₋₆alkyl, —NH₂, —NH—C₁₋₆alkyl, —(C═O)O—C₁₋₆alkyl, or phenyl, whereinthe phenyl is unsubstituted or substituted with C₁₋₆alkyl, halogen, orC₁₋₆alkyl-OH, (4) C₃₋₆cycloalkyl, which is unsubstituted or substitutedwith C₁₋₆alkyl, halogen, hydroxyl, —O—C₁₋₆alkyl, —NH₂, —NH—C₁₋₆alkyl,—(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl is unsubstituted orsubstituted with C₁₋₆alkyl, halogen, or C₁₋₆alkyl-OH, (5) —O—C₁₋₆alkyl,which is unsubstituted or substituted with halogen, hydroxyl or phenyl,and (6) —(C═O)O—C₁₋₆alkyl, (7) —CN, (8) —(C═O)NH₂, (9)—(C═O)NH—C₁₋₆alkyl, and (10) —(C═O)NH—O—C₁₋₆alkyl; R⁶ is selected fromthe group consisting of: (1) hydrogen, (2) halogen, (3) C₁₋₆alkyl, whichis unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl,—NH₂, —NH—C₁₋₆alkyl, —(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl isunsubstituted or substituted with C₁₋₆alkyl, halogen, or C₁₋₆alkyl-OH,(4) C₃₋₆cycloalkyl, which is unsubstituted or substituted withC₁₋₆alkyl, halogen, hydroxyl, —O—C₁₋₆alkyl, —NH₂, —NH—C₁₋₆alkyl,—(C═O)O—C₁₋₆alkyl, or phenyl, wherein the phenyl is unsubstituted orsubstituted with C₁₋₆alkyl, halogen, or C₁₋₆alkyl-OH, (5) —O—C₁₋₆alkyl,which is unsubstituted or substituted with halogen, hydroxyl or phenyl,and (6) —(C═O)O—C₁₋₆alkyl, (7) —CN, (8) —(C═O)NH₂, (9)—(C═O)NH—C₁₋₆alkyl, and (10) —(C═O)NH—O—C₁₋₆alkyl; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1 of the formula Ia:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1 of the formula Ib:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1 or a pharmaceutically acceptable salt thereof wherein R^(1a), R^(1b)and R^(1c) are independently selected from the group consisting of: (1)hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which isunsubstituted or substituted with halogen, hydroxyl or phenyl, (5)—O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl, (6) —CN, and (7) heteroaryl, wherein heteroaryl isselected from triazolyl, tetrazolyl, oxazolyl, pyrrolyl, imidazolyl,indolyl, pyridyl, and pyrimidinyl, which is unsubstituted or substitutedwith halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.
 5. The compoundof claim 1 or a pharmaceutically acceptable salt thereof wherein R^(1c)is hydrogen, and R^(1a) and R^(1b) are independently selected from thegroup consisting of: (1) hydrogen, (2) fluoro, (3) chloro, (4) bromo,(5) methyl, (6) ethyl, (7) trifluoromethyl, and (8) heteroaryl, whereinheteroaryl is selected from triazolyl, oxazolyl, pyrrolyl, imidazolyl,indolyl, pyridyl, and pyrimidinyl.
 6. The compound of claim 1 or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of: (1) hydrogen, (2) bromo, (3) methyl, (4)—C(CH₃)₂OH, (5) —CH(OH)CH₃, (6) —C(CH₃)(OH)CH₂CH₃, (7) —CH₂OCH₃, (8)cyclopropyl, and (9) phenyl.
 7. The compound of claim 1 or apharmaceutically acceptable salt thereof wherein R⁵ is —C(CH₃)₂OH. 8.The compound of claim 1 or a pharmaceutically acceptable salt thereofwherein R⁶ is selected from the group consisting of: (1) hydrogen, (2)bromo, (3) methyl, (4) trifluoromethyl, (5) —CH(CH₃)₂, and (6) phenyl.9. The compound of claim 1 or a pharmaceutically acceptable salt thereofwherein R⁶ is methyl.
 10. A compound which is selected from the groupconsisting of:(R)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-ethoxypyridin-3-yl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-cyclopropylphenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2-isopropoxypyridin-3-yl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2-(pyrrolidin-1-yl)phenyl)methanone;(R)-(2-ethoxyphenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2-(trifluoromethoxy)phenyl)methanone;(R)-(2-(1H-pyrazol-1-yl)phenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2-(2,2,2-trifluoroethyl)pyridin-3-yl)methanone;(R)-(2-(2,2-difluoroethyl)phenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-(1H-pyrazol-1-yl)pyridin-3-yl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2-phenylpyridin-3-yl)methanone;(R)-(2-(difluoromethoxy)phenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-(2,2-difluoroethoxy)pyridin-3-yl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2-(2,2,2-trifluoroethoxy)phenyl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin1-yl)(2-(2,2,2-trifluoroethyl)phenyl)methanone;(R)-(2-cyclopropyl-6-methoxypyridin-3-yl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-(2,2-difluoroethoxy)phenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin1-yl)(3-(pyridin-2-yl)pyrazin-2-yl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(3-(pyrrolidin-1-yl)pyrazin-2-yl)methanone;(R)-(2-cyclobutylphenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(3-phenylpyridin-2-yl)methanone;(R)-(3-(1H-pyrazol-1-yl)pyrazin-2-yl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(2-(2,2-difluorocyclopropyl)phenyl)((R)-2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-(2H-tetrazol-2-yl)phenyl)(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin-1-yl)(2-propylphenyl)methanone;(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone; and(R)-(2-((4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)methyl)piperidin1-yl)(2-(pyrimidin-2-yl)phenyl)methanone; or a pharmaceuticallyacceptable salt thereof.
 11. A pharmaceutical composition whichcomprises an inert carrier and a compound of claim 1 or apharmaceutically acceptable salt thereof.